Cyclosporin

Tacrolimus

Sirolimus

Mycophenolate mofetil

Azothioprine

Methotrexate

Cyclophosphamide

Antithymocyte globulin

Rho(D) Immune globulin

Muromonab-CD3

Basiliximab

Daclizumab

Alafacept

Etanercept

Adalimumab

Golimumab

Infliximab

Certolizumab

etanercept

adalimumab

golimumab

infliximab

certolizumab

Glucocorticoid

Mechanism:

- interferes with cell cycle of lymphoid cells

- inhibits inflammatory mediator production (IL-2)

Clinical Use:

- organ rejection

- graft vs. host disease

- Rheumatoid Arthritis

- Inflammatory bowel disease

Side Effects:

- protein breakdown

- hyperglycemia

- iatrogenic Cushing's syndrome

- avascular/aseptic osteonecrosis

- myopathy

- hypertension

Calcineurin Inhibitor

Mechanism:

- blocks production of IL-2 via binding of cyclophilin (CpN) and then inhibiting calcineurin thus preventing NFAT from entering nucleus → ↓ T-cell proliferation 

- metabolized by CYP3A

Clinical Use:

- organ transplant

- GVHD (hemopoetic)

- Autoimmune disorders

Side effects:

- nephrotoxicity

- hypertension

Drug interactions:

- synergistic nephrotoxicity when co-administered with tacrolimus

- drugs inhibiting CYP3A → ↑ cyclosporin

   ~ glucocorticoids

- drugs stimulating CYP3A → ↓ cyclosporin

   ~ St John's wort, rifamycin

Calcineurin Inhibitor

Mechanism:

- binds FKBP-12 leading to calcineurin inhibition and prevention of NFAT translocation to nucleus thus preventing IL-2 production → ↓ T-cell proliferation

- metabolized by CYP3A

Clinical Use:

- acute organ transplant rejection (liver)

- GVHD

Side Effects:

- nephrotoxicity

- hyperglycemia

- neurotoxicity

Drug interactions:

- synergistic nephrotoxicity with calcineurin inhibitors

- exhibits same drug interactions as cyclosporine due to metabolism by CYP3A

Antiproliferative and Antimetabolic

Mechanism:

- binds FKBP-12 leading to the inhibtion of mTOR thus preventing a kinase cascade thus arresting the cell cycle progression

Clinical Use:

- prevent organ transplant rejection in combination with glucocorticoids and calcineurin inhibitors

- if nephrotoxicity must be managed, use mycophenolate mofetil instead of calcineurin inhibitor

Side effects:

- hyperlipidemia

- bone marrow suppression

     ~anemia, thrombocytopenia, leukopenia

Drug Interactions:

- cyclosporin ↑ sirolimus-induced hyperlipidemia and myelosuppression

- sirolimus aggrevates cyclosporine-induced nephrotoxicity

Antiproliferative and antimetabolic

Mechanism:

- inhibits IMP dehydrogenase used in guanine nucleotide metabolism → ↓ T and B cell proliferation

- rapidly hydrolyzed to active form: mycophenolic acid (MPA)

Clinical Use:

- prevent organ transplant rejection in combo with glucocorticoids and calcineurin inhibitors

Side effects:

- myelosuppression: leukopenia

- GI: diarrhea

- ↑ in some infections (cytomegalovirus)

Drug interactions:

- Do not use with Azothioprine

- Al or MgOH decreases GI absorption

- works well with cyclosporin, famethoxazole/trimethoprim

- enterohepatic circulation leads to decreased MPA levels

- acyclovir and gangcyclovir may increase MPA and antiviral concentrations in the blood

Antiproliferative and Antimetabolic

Mechanism:

- metabolized into fraudulent nucleotide (6-thio-IMP) then incorporated into DNA blocking transcription and thus cell proliferation

Clinical use:

- prevent organ transplant rejection

- Rheumatoid arthritis

- induction and maintenance of ulcerative colitis and Crohn's disease

Side effects: dose related

- myelosuppression: leukopenia, thrombocytopenia, anemia

- hepatic toxicity

- general chemotherapy side effects

Drug interactions:

- drugs interfering with Xanthine oxidase lead to severe leukopenia

Antiproliferative and Antimetabolic

Mechanism:

- inhibits dihydrofolate reductase thus interfering with folic acid metabolism thus decreasing thymidylate, purine nucleotides, and ser/met amino acids leading to decreased RNA, DNA, and protein synthesis thus impairing immune cell function/proliferation

Clinical use:

- at high doses it is a chemotherapeutic drug

- induce and maintain IBD

- rheumatoid arthritis

- GVHD

- psoriasis

Side effects:

- high dose = myelosuppression → megaloblastic anemia, alopecia, mucositis

- hepatic damage

- nausea, vomiting, diarrhea, mucosal ulcers

Drug interactions:

- cyclosporine elevates methotrexate levels

Antiproliferative and Antimetabolic

Mechanism:

- alkylating agent of proteins, DNA/RNA leading to cell toxicity

- suppresses T and B cell function 30-40%

- metabolized by CYP2B

Clinical use:

- broad spectrum cancer chemo

- organ rejection after transplant (high dose over several days)

- Autoimmune disease

- NO GVHD prevention

- Wegner's granulomatosis

Side effects:

- dose related toxicities in rapid growing tissue; nausea, vomiting

Polyclonal Antibody

Mechanism:

- binds CD2, 3, 4, 8, 11a, 18, 25, 44, 45 and HLA class 1 and 2 molecules which leads to cytotoxicity via complement activation and cell-mediated destruction of the bound T-lymphocytes

- some block lymphocyte function

Uses:

- induction of immunosuppression leading to a decrease in T-cell count within 2 days

- treat acute renal transplant rejection

Side effects:

- fever

- chills

- leukopenia

- thrombocytopenia

- HAMA reaction

Polyclonal antibody

Mechanism:

- isolated IgG specific for Rh factor is taken from humans and injected into pregnant women to clear maternal blood [Rh (-)] of fetal Rh (+) blood so that an immune response is not generated and thus no B-cell response is generated

Clincal use:

- treat Rh incompatibility to prevent hemolytic disease of the newborn

Side effects:

- injection site discomfort

- low-grade fever

- transmission of infectious disease from donor plasma

Monoclonal antibody

Mechanism:

- binds to CD3 and blocks T-cell function of antigen recognition; causes rapid T-cell depletion and cytokine release

Clinical use:

- treat acute allograft rejection and steroid resistant rejection

Side effects:

- cytokine release syndrome

- HAMA reaction

- aseptic meningitis

- infection susceptibility

- increase in lymphoma in combo with cyclosporin

Monoclonal Antibody

Mechanism:

- fused IgG Fc region with CD2-binding portion of LFA-3 leading to the blockage of CD2 and thus blocking proliferation and communication of the T cell

Clinical use:

- plaque psoriasis

Monoclonal Antibody

Mechanism:

- fusion of Fc region with TNF receptor  allowing binding of TNF-α & β leading to the suppression of inflammatory cytokines and adhesion molecules

Clinical uses:

- rheumatoid arthritis

Adalimumab

Golimumab

Monoclonal Antibody

Mechanism:

- human Ab recognizing TNF-α only thus blocking TNF-α from binding receptor and preventing inflammatory cytokines and adhesion molecules from being produced

Clinical use:

- rheumatoid arthritis

Infliximab

Certolizumab

Monoclonal antibody

Mechanism:

- blocks TNF-α from binding to receptor and thus suppressing inflammatory cytokines and adhesion molecules

Clinical use:

- rheumatoid arthritis

- Crohn's disease

Side effects:

- Infusion reaction- fever, hives, hypotension, dyspnea

- Injection site reaction

- Infections are potentially deadly due to lack of inflammation 

- ↑ in occurrence in lymphoma

Monoclonal antibody

Mechanism:

- binds to CD52 on malignant and nonmalignant T and B lymphocytes → NK cell, monocyte/macrophage and some granulocytes to destroy and deplete leukemic and normal cells by antibody-dependent lysis

Clinical uses:

- B-cell chronic lymphocytic leukemia in patients who fail fludarabine therapy

Side effects:

- hematologic toxicity- lymphopenic, neutropenic, anemic, thrombocytopenic, opportunistic infections

Monoclonal antibody

Mechanism:

- binds CD20 (pan-B cell protein) leading to complement-mediated lysis, Ab-dependent cellular toxicity, and induction of apoptosis in malignant lymphoma cells 

Clinical use:

- relapse of refractory low-grade follicular B cell non-Hodgkins lymphoma

  ~ used in conjunction with Ibritumomab tiuxetan = binds CD20 (mouse Ab)

Sequential Immunotherapy

 -Treatments

 -Goal

Induction:

- pretransplant and immediate post-transplant period

Treatments:

- muromonab-CD3

- anti-CD25 monoclonal antibodies

- polyclonal antilymphocyte antibodies

Goal:

- enable engraftment without nephrotoxic calcineurin inhibitors

Multiple drugs simultaneously

Treatments:

- calcineurin inhibitors

- glucocorticoids

- mycophenolate mofetil (discrete sites of T-cell activation)

Goal:

- peaceful coexistence with minimal tissue issues

T-cells already activated thus agents that prevent activation of T-cells are ineffective

Treatment:

- high dose glucocorticoids

- polyclonal antilymphocyte antibodies

- muromonab-CD3 antibody

- cyclophosphamide

Goal:

- prevent chronic rejection